When it was initially formed in 1954 it was formed with the goal of basic research including trying to understand in Hughes words: "genesis of life itself". Despite its lofty principles, in the early days it was viewed by some as largely a tax haven for Hughes' huge personal fortune. For many years the Institute grappled with maintaining its non-profit status, the Internal Revenue Service challenged its "charitable" status which made it tax-exempt. Partly in response to such claims, starting in the late 1950s it began with funding 47 investigators researching at eight different institutions, however, it remained a modest enterprise for several decades. In fact it was not until after Hughes' death in 1976 that the Institute's profile increased from annual budget of $4 million in 1975 to $15 million by 1978. In this period it refocused its mission to focus on genetics, immunology and the rapidly growing field of molecular biology.
Since Hughes died without a will as the sole trustee of the HHMI, the Institute was involved in lengthy court proceedings to determine whether it would benefit from Hughes fortune. In 1984, a court appointed new trustees to the Hughes estate. These trustees sold Hughes Aircraft to General Motors and part of the $5 billion proceeds caused the institute to grow dramatically. As of 2003, the Institute funds biomedical research throughout the United States and the world. As of early 2002 the endowment of the Institute was valued approximately $11 billion, making it the second-largest philanthropy in the country, behind the Bill and Melinda Gates Foundation.